1. Field of the Invention
This invention is directed to new and improved long-acting narcotic antagonists and non-addictive analgesics. More particularly, the invention is directed to opioid receptor site-directed alkylating agents, and to the method of synthesizing the same.
2. The Prior Art
Narcotic antagonists have received considerable attention over the past several years, particularly since the discovery of the endorphins. Besides being useful as prophylactic agents in the management of narcotic addiction and as nonaddictive analgesics, they have more recently been employed on an experimental basis in the treatment of mental illness. Additionally, the report that .beta.-endorphin-induced stimulation of food intake is blocked by naloxone also suggests that narcotic antagonists might have potential as appetite suppressants. The action of enkephalin and enkephalin analogues as potent hypotensive agents also suggests that nonpeptide analogues might find use in the treatment of hypertension.
For these reasons, compounds with narcotic antagonist activity which specifically antagonize the actions of narcotics or of endogenous peptides (e.g., endorphins) might find application in the treatment of a variety of conditions. Also, properly modified agonists or mixed agonist-antagonists conceivably might give rise to new classes of anti-hypertensive agents and anti-obesity drugs.
With the accumulation of evidence which supports the concept of multiple opioid receptors and their classification into subtypes, it is becoming apparent that exogenously administered opioids mediate their manifold effects through several types of receptors.
Our approach to designing compounds that are selective and have prolonged activities is based upon the attachment of alkylating groups to ligands which are recognized by opioid receptors. The formation of a covalent bond with the receptor will enable the drug to remain in the receptor locus and thereby exert its effects for extended periods. Such drugs would not be subject to the normal disposition processes which ordinarily terminate their action.
An important feature in the design of such drugs takes into account the location of the nucleophile which forms the covalent bond with the reactive group. As the presence of the reactive moiety does not necessarily lead o covalent association after a drug-receptor complex is formed, it is apparent that the position of attachment of the alkylating group on to the pharmacophore is of critical importance. Thus, while there have been a number of attempts to design opioid receptor site-directed alkylating agents, only recently has this goal been successfully executed. This was demonstrated with the ultralong-acting narcotic antagonist, chlornaltrexamine (CNA) [Portoghese et al, J. Med. Chem., 21, 598 (1978) and Portoghese et al, J. Med. Chem., 22, 168 (1979)] and the irreversible agonist, chloroxymorphamine (COA) [Caruso et al, Science, 204, 316 (1979)]. These reports demonstrated the presence of a receptor nucleophile proximal to the alkylating group on the drugs.
Once the location of the receptor nucleophile is known, it should be possible to design much more selective compounds which would alkylate selected subclasses of opioid receptors. Presumably, this selectivity would be a consequence of differences in the nature and location of the nucleophiles in different receptors. The present invention is directed to compounds produced as the result of such an approach.